Differential Impact of Fluid Shear Stress and YAP/TAZ on BMP/TGF‐β Induced Osteogenic Target Genes

Reichenbach, Maria; Mendez, Paul-Lennard; Madaleno, Carolina da Silva; Ugorets, Vladimir; Rikeit, Paul; Boerno, Stefan; Jatzlau, Jerome; Knaus, Petra

doi:10.1002/adbi.202000051

Cited by 12 publications

(3 citation statements)

References 99 publications

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“…Compelling evidence suggests that cells respond to liquid shear forces through the Hippo pathway. 92,93 The first study that uncovered the relationship between liquid shear forces and the regulation of the Hippo pathway revealed that increased fluid flow promoted the expression of YAP and was associated with osteogenesis and a decrease in adipogenesis in mesenchymal stem cells (MSCs). In Fig.…”

Section: Key Components Of the Hippo Pathwaymentioning

confidence: 99%

The Hippo signalling pathway and its implications in human health and diseases

Lan

et al. 2022

Sig Transduct Target Ther

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As an evolutionarily conserved signalling network, the Hippo pathway plays a crucial role in the regulation of numerous biological processes. Thus, substantial efforts have been made to understand the upstream signals that influence the activity of the Hippo pathway, as well as its physiological functions, such as cell proliferation and differentiation, organ growth, embryogenesis, and tissue regeneration/wound healing. However, dysregulation of the Hippo pathway can cause a variety of diseases, including cancer, eye diseases, cardiac diseases, pulmonary diseases, renal diseases, hepatic diseases, and immune dysfunction. Therefore, therapeutic strategies that target dysregulated Hippo components might be promising approaches for the treatment of a wide spectrum of diseases. Here, we review the key components and upstream signals of the Hippo pathway, as well as the critical physiological functions controlled by the Hippo pathway. Additionally, diseases associated with alterations in the Hippo pathway and potential therapies targeting Hippo components will be discussed.

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Section: Key Components Of the Hippo Pathwaymentioning

confidence: 99%

The Hippo signalling pathway and its implications in human health and diseases

Lan

et al. 2022

Sig Transduct Target Ther

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“…To elucidate the crosstalk between mechanical and biochemical signaling pathways in the regulation of CCN expression during bone remodeling, Reichenbach et al demonstrated that fluid shear stress acts collaboratively with YAP/TAZ on the induction of BMP/TGF‐β target genes, including CCN1 and CCN2. (Reichenbach et al 2021). However, the mechanisms of fluid shear stress‐regulated CCN family gene induction involving interactions between transcription factors/co‐activators are still largely unknown.…”

Section: Ccn Family Members Mediate Fluid Shear Stress‐induced Bone R...mentioning

confidence: 98%

The regulation and functions of the matricellular CCN proteins induced by shear stress

Wang

Weng

2023

J. Cell Commun. Signal.

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Shear stress is a frictional drag generated by the flow of fluid, such as blood or interstitial fluid, and plays a critical role in regulating cellular gene expression and functional phenotype. The matricellular CCN family proteins are dynamically regulated by shear stress of different flow patterns, and their expression significantly alters the microenvironment of cells. Secreted CCN proteins mainly bind to several cell surface integrin receptors to mediate their diverse functions in regulating cell survival, function, and behavior. Gene-knockout studies indicate major functions of CCN proteins in the cardiovascular and skeletal systems, the two primary systems in which CCN expressions are regulated by shear stress. In the cardiovascular system, the endothelium is directly exposed to vascular shear stress. Unidirectional laminar blood flow generates laminar shear stress, which promotes a mature endothelial phenotype and upregulates anti-inflammatory CCN3 expression. In contrast, disturbed flow generates oscillatory shear stress, which induces endothelial dysfunction through the induction of CCN1 and CCN2. Shear-induced CCN1 binds to integrin α6β1 and promotes superoxide production, NF-κB activation, and inflammatory gene expression in endothelial cells. Although the interaction between shear stress and CCN4-6 is not clear, CCN 4 exhibits a proinflammatory property and CCN5 inhibits vascular cell growth and migration. The crucial roles of CCN proteins in cardiovascular development, homeostasis, and disease are evident but not fully understood. In the skeletal system, mechanical loading on bone generates shear stress from interstitial fluid in the lacuna-canalicular system and promotes osteoblast differentiation and bone formation. CCN1 and CCN2 are induced and potentially mediate fluid shear stress mechanosensing in osteocytes. However, the exact roles of interstitial shear stress-induced CCN1 and CCN2 in bone are still not clear. In contrast to other CCN family proteins, CCN3 inhibits osteoblast differentiation, although its regulation by interstitial shear stress in osteocytes has not been reported. The induction of CCN proteins by shear stress in bone and their functions remain largely unknown and merit further investigation. This review discusses the expression and functions of CCN proteins regulated by shear stress in physiological conditions, diseases, and cell culture models. The roles between CCN family proteins can be compensatory or counteractive in tissue remodeling and homeostasis.

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“…111 Osteoclasts subjected to fluid sheer stress display YAP/TAZ -dependent BMP2/TGF-β-SMAD2/3 gene transcription and stability and SMAD1 degradation. 112 Recently, BMP6 has been found to activate the Hippo pathway, inhibiting YAP/TAZ activity by retaining it in the cytoplasm, allowing SMAD7 to be expressed and inhibit SMAD3. 113 In contexts of PH-associated vascular stiffness, YAP/ TAZ or GLS1 knockdown in primary human PAECs and PASMCs reduced cell proliferation and migration.…”

Section: Reviewmentioning

confidence: 99%

BMPR2 Mutation and Metabolic Reprogramming in Pulmonary Arterial Hypertension

Cuthbertson

Morrell

Caruso

2023

Circulation Research

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Pulmonary arterial hypertension forms the first and most severe of the 5 categories of pulmonary hypertension. Disease pathogenesis is driven by progressive remodeling of peripheral pulmonary arteries, caused by the excessive proliferation of vascular wall cells, including endothelial cells, smooth muscle cells and fibroblasts, and perivascular inflammation. Compelling evidence from animal models suggests endothelial cell dysfunction is a key initial trigger of pulmonary vascular remodeling, which is characterised by hyperproliferation and early apoptosis followed by enrichment of apoptosis-resistant populations. Dysfunctional pulmonary arterial endothelial cells lose their ability to produce vasodilatory mediators, together leading to augmented pulmonary arterial smooth muscle cell responses, increased pulmonary vascular pressures and right ventricular afterload, and progressive right ventricular hypertrophy and heart failure. It is recognized that a range of abnormal cellular molecular signatures underpin the pathophysiology of pulmonary arterial hypertension and are enhanced by loss-of-function mutations in the BMPR2 gene, the most common genetic cause of pulmonary arterial hypertension and associated with worse disease prognosis. Widespread metabolic abnormalities are observed in the heart, pulmonary vasculature, and systemic tissues, and may underpin heterogeneity in responsivity to treatment. Metabolic abnormalities include hyperglycolytic reprogramming, mitochondrial dysfunction, aberrant polyamine and sphingosine metabolism, reduced insulin sensitivity, and defective iron handling. This review critically discusses published mechanisms linking metabolic abnormalities with dysfunctional BMPR2 (bone morphogenetic protein receptor 2) signaling; hypothesized mechanistic links requiring further validation; and their relevance to pulmonary arterial hypertension pathogenesis and the development of potential therapeutic strategies.

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Differential Impact of Fluid Shear Stress and YAP/TAZ on BMP/TGF‐β Induced Osteogenic Target Genes

Cited by 12 publications

References 99 publications

The Hippo signalling pathway and its implications in human health and diseases

The Hippo signalling pathway and its implications in human health and diseases

The regulation and functions of the matricellular CCN proteins induced by shear stress

BMPR2 Mutation and Metabolic Reprogramming in Pulmonary Arterial Hypertension

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